The development of an effective malaria vaccine requires the identification of the effector mechanisms which function during a protective immune response. CD4+ helper and cytotoxic T cells, derived from cells of sporozoite-immunized human volunteers and chimpanzees, recognize epitopes located in the repeat and non-repeat regions of the P. falciparum and P. vivax circumsporozoite (CS) protein. Studies in the rodent malaria model suggests that, in addition to their helper cell function, CD4+ T cells may play a direct role in immune resistance, either by lysing EEF infected hepatocytes or by releasing lymphokines that inhibit the growth of the parasite within the liver cell. In order to investigate CD4+ T cell mediated immunity directed against the exoerythrocytic stages of malaria, we will determine whether native CS protein, released by the motile sporozoite or the EEF within infected hepatocytes, is processed and presented by Class II on hepatocytes, or non- parenchymal cells, for recognition by primate CS-specific CD4+ cells in vitro. Since the role of primate CD4+ effector T cells cannot be studied in vivo, due to ethical and practical limitations, we will transplant human hepatocytes and primate CD4+ T cells into SCID mice. Following injection of P. falciparum or P. vivax sporozoites, we will determine whether the engrafted SCID mouse provides a satisfactory in vivo model for the study of effector functions of primate T cell clones specific for the CS protein. In order to determine whether cytotoxic CD4+ T cells can be induced with a synthetic vaccine, we will immunize mice with Multiple Antigen Peptide systems (MAPs) containing the CD4+ CTL epitope of the P. falciparum CS protein. The MAPs immunized mice will also be used to determine whether this epitope can also induce T helper cells for the production of anti- sporozoite antibodies. In order to directly assay the in vivo role of CS specific CD4+ cells, we will use P. yoelii sporozoite-immunized transgenic mice, that lack CD8+ T cells, to determine whether CD4+ T cells can protect against viable sporozoite challenge: These in vitro and in vivo studies will provide information on immunity to exoerythrocytic stages of the malaria parasite and hopefully facilitate the rational design of a malarial vaccine capable of inducing cytotoxic and/or lymphokine-mediated T cell effector mechanisms, as well as high levels of humoral immunity.